Retroviruses cause lethal diseases in humans such as acquired immunodeficiency syndrome and T-cell leukemia by defeating host immune responses. There is large body of evidence suggesting that genetic variations in the human population influence the disease outcome in infected individuals. While studies of inherited resistance to retroviruses in human populations are enormously complicated, the variations in the susceptibility of inbred mice to retroviral infections make the mouse an excellent model for mapping mammalian resistance and susceptibility genes. Like HIV, Mouse Mammary Tumor Virus (MMTV) and Murine Leukemia Virus (MuLV) are retroviruses that have evolved numerous mechanisms to avoid elimination by the immune systems of susceptible mice. However, the viruses fail to replicate in I/LnJ mice as these mice infected with either virus produce virus-neutralizing antibodies, sustain this response throughout their life, and prevent infection of their progeny by coating secreted virions with anti- virus antibodies. We established that antibody-mediated interference with viral entry is the sole factor inhibiting virus transmission in I/LnJ mice. Generation of virus-neutralizing Abs in both systems required IFN-g and was independent of IL-12. This unique mechanism of retroviral resistance inherited by I/LnJ mice is controlled by a single recessive gene, virus infectivity controller 1 (vic1), mapped to a 17.1 Mb region of Chromosome 17 outside the major histocompatibility locus. Using BALB/cJ mice congenic for the vic1 I/LnJ locus, we found that in addition to controlling the anti-virus humoral immune response, vic1 also influences the production of a virus specific cytotoxic response that prevents disease induction by the retroviruses. The vic1-mediated resistance mechanism bears a resemblance to the well-known resistance mechanism against MuLV controlled by the resistance to Friend virus 3 (rfv3) gene. However, the two resistance mechanisms are clearly different from one another, since the rfv3 gene has been mapped to Chromosome 15 and confers resistance to MuLV but not to MMTV. Thus, we have identified a unique virus resistance mechanism which controls immunity against retroviruses from two distinct genera. We propose to positional clone the vic1 gene. The elucidation of the mechanism of retrovirus resistance in I/LnJ mice is of fundamental importance and will ultimately lead to increased knowledge about variations in susceptibility to viral infections in humans and to development of the most effective vaccines against human viruses, and other diseases.